muscle inv & metastatic bc 2010

8/12/2019 Muscle Inv & Metastatic BC 2010

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Guidelines on

Bladder

Cancer

Muscle-invasive

and Metastatic

A. Stenzl (Chairman), N.C. Cowan, M. De Santis, M. Kuczyk,

A.S. Merseburger, M.J. Ribal, A. Sherif, J.A. Witjes

European Association of Urology 2010


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TABLE OF CONTENTS PAGE

1 INTRODUCTION 5 1.1 The guideline 5 1.2 Methodology 5 1.2.1 Data identification 5 1.2.2 Publication history 5

1.3 Summary of updated information 5 1.4 Acknowledgements 5 1.5 Reference 6

2 EPIDEMIOLOGY AND RISK FACTORS 6 2.1 Epidemiology 6 2.2 Risk factors for bladder cancer 6 2.2.1 Tobacco smoking 6

2.2.2 Occupational exposure to chemicals 7 2.2.3 Radiation therapy 7 2.2.4 Dietary factors 7 2.2.5 Chronic urinary tract infection 7

2.2.6 Bladder schistosomiasis 7 2.2.7 Chemotherapy 7 2.2.8 Synchronous and metachronous upper urinary tract tumours 8 2.2.9 Gender 8 2.3 Conclusions about epidemiology and risk factors 8 2.4 Recommendation for risk factors 9 2.5 References 9

3 CLASSIFICATION 11 3.1 Tumour, Nodes, Metastases classification 11 3.2 Histological grading of non-muscle-invasive bladder tumours 11 3.2.1 WHO grading 11 3.3 Pathology 12 3.3.1 Urologist handling of specimens 12 3.3.2 Pathologist handling of specimens 12 3.3.3 Pathology of muscle-invasive bladder cancer 12 3.3.4 Recommendations for the assessment of tumour specimens 13 3.4 References 13

4 DIAGNOSIS AND STAGING 14 4.1 Diagnosis 14 4.1.1 Symptoms 14 4.1.2 Physical examination 14 4.1.3 Imaging 14 4.1.3.1 CT imaging 14

4.1.3.2 Intravenous urography (IVU) 14 4.1.3.3 Ultrasonography 14 4.1.3.4 Recommendations for staging in verified bladder tumours 14 4.1.4 Urinary cytology and urinary markers 14 4.1.5 Cystoscopy 15 4.1.6 Transurethral resection (TUR) of invasive bladder tumours 15 4.1.7 Random bladder and (prostatic) urethral biopsy 15 4.1.8 Second resection 15 4.1.9 Concomitant prostate cancer 15 4.1.10 Recommendations for primary assessment of presumably

invasive bladder tumours 16 4.2 Imaging for staging in verified bladder tumours 16

4.2.1 Local staging of invasive bladder cancer 16 4.2.1.1 MR imaging for local staging of invasive bladder cancer 16 4.2.1.2 CT imaging for local staging of invasive bladder cancer 17 4.2.2 Imaging of nodal involvement 17

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4.2.3 Extravesical urothelial carcinoma 17 4.2.4 Distant metastases other than lymph nodes 17 4.2.5 Conclusions for staging of verified bladder tumour 17 4.2.6 Recommendations for staging of verified bladder tumour 17 4.3 References 18

5 TREATMENT FAILURE OF NON-MUSCLE-INVASIVE BLADDER CANCER 21

5.1 High-risk non-muscle-invasive urothelial carcinoma 21 5.2 Carcinoma in situ 22 5.3 Recommendations for treatment failure of NMIBC 22 5.4 References 22

6 NEOADJUVANT CHEMOTHERAPY 24 6.1 Conclusions for neoadjuvant chemotherapy 25 6.2 Recommendations for neoadjuvant chemotherapy 26 6.3 References 26

7 RADICAL SURGERY AND URINARY DIVERSION 28 7.1 Removal of the tumour-bearing bladder 28

7.1.1 Background 28 7.1.2 Timing and delay of cystectomy 28 7.1.3 Indications 28 7.1.4 Technique and extent 29 7.1.5 Laparoscopic/robotic-assisted laparoscopic cystectomy (RALC) 29 7.2 Urinary diversion after radical cystectomy 30 7.2.1 Preparations for surgery 30 7.2.2 Ureterocutaneostomy 30 7.2.3 Ileal conduit 30 7.2.4 Continent cutaneous urinary diversion 30 7.2.5 Ureterocolonic diversion 31 7.2.6 Orthotopic neobladders 31 7.3 Morbidity and mortality 31 7.4 Survival 31 7.5 Conclusions on urinary diversion after radical cystectomy 32 7.6 Recommendations for radical cystectomy and urinary diversion 32 7.6.1 Recommendations for radical surgery 32 7.6.2 Recommendations for urinary diversion 32 7.7 References 32

8 NON-RESECTABLE TUMOURS 37 8.1 Palliative cystectomy for muscle-invasive bladder carcinoma 37 8.2 Conclusions on non-resectable tumours 37 8.3 Recommendations for non-resectable tumours 38 8.4 References 38

9 NEOADJUVANT RADIOACTIVITY IN MUSCLE-INVASIVE BLADDER CANCER 38 9.1 Pre-operative radiotherapy 38 9.1.1 Retrospective studies 38 9.1.2 Randomised studies 38 9.1.3 Effect of pre-treating patients with neoadjuvant radiotherapy before cystectomy 39 9.2 Conclusions for pre-operative radiotherapy 39 9.3 Recommendations for pre-operative radiotherapy 40 9.4 References 40

10 BLADDER-SPARING TREATMENTS FOR LOCALISED DISEASE 41 10.1 Transurethral resection of bladder tumour (TURB) 41

10.1.1 Conclusion and recommendation for TURB 41 10.1.2 References 41 10.2 External beam radiotherapy 42 10.2.1 Conclusions on external beam radiotherapy 42

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10.2.2 Recommendation for external beam radiotherapy 42 10.2.3 References 42 10.3 Chemotherapy 43 10.3.1 Conclusion and recommendation for chemotherapy for localised disease 44 10.3.2 References 44 10.4 Multimodality treatment 45 10.4.1 Conclusions on multimodality treatment 46

10.4.2 Recommendations for multimodality treatment 46 10.4.3 References 46

11 ADJUVANT CHEMOTHERAPY 47 11.1 Conclusion and recommendation for adjuvant chemotherapy 47 11.2 References 47

12 METASTATIC DISEASE 48 12.1 Prognostic factors and treatment decisions 48 12.2 Single-agent chemotherapy 49 12.3 Standard first-line chemotherapy for fit patients 49 12.4 Carboplatin-containing chemotherapy in fit patients 49

12.5 Non-platinum combination chemotherapy 49 12.6 Chemotherapy in patients unfit for cisplatin 50 12.7 Second-line treatment 50 12.8 Low-volume disease and post-chemotherapy surgery 50 12.9 Bisphosphonates 51 12.10 Conclusions for metastatic disease 51 12.11 Recommendations for metastatic disease 51 12.12 References 52

13. QUALITY OF LIFE 57 13.1 Conclusions on quality of life 57 13.2 Recommendations on quality of life 58 13.3 References 58

14 FOLLOW-UP 60 14.1 Site of recurrence 60 14.1.1 Distant recurrences 60 14.1.2 Secondary urethral tumours 60 14.1.3 Conclusions and recommendations for specific recurrence sites 61 14.2 References 61

15 ABBREVIATIONS USED IN THE TEXT 63

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1. INTRODUCTION

1.1 The guideline

The European Association of Urology (EAU) Guideline Panel for Muscle-invasive and Metastic Bladder Cancer(MIBC) has prepared these guidelines to help urologists assess the evidence-based management of MIBC andto incorporate guideline recommendations into their clinical practice. The EAU Guidelines Panel consists of aninternational multidisciplinary group of experts in this field.

It is evident that optimal treatment strategies for MIBC require the involvement of a specialistmultidisciplinary team and a model of integrated care to avoid fragmentation of patient care.

1.2 Methodology

1.2.1 Data identification

Comprehensive literature searches were designed for each section of the MIBC guideline with the help of anexpert external consultant. Following detailed internal discussion, searches were carried out in the CochraneLibrary database of Systematic Reviews, the Cochrane Library of Controlled Clinical Trials, and Medline andEmbase on the Dialog-Datastar platform. The searches used the controlled terminology of the respectivedatabases. Both MesH and EMTREE were analysed for relevant terms; urinary bladder neoplasms (Medline)and bladder cancer (Embase) were the narrowest single terms available. Extensive use of free text ensured the sensitivity of the searches, although the subsequent

concomitant workload for panel members having to assess the substantial body of literature greatly increased. Search strategies covered the last 10 years for Medline and for Embase in most cases. Randomisedcontrolled trial (RCT) strategies used were based on Scottish Intercollegiate Guidelines Network (SIGN) andModified McMaster/Health Information Research Unit (HIRU) filters for RCTs, systematic reviews and practiceguidelines on the OVID platform. Results of all searches were scan-read by panel members. In many casesthere was a high numbers needed to read due to the sensitivity of the search.

There is clearly a need for continuous re-evaluation of the information presented in the currentguideline by an expert panel. It must be emphasised that the current guideline contains information for thetreatment of an individual patient according to a standardised approach.

The level of evidence and grade of recommendation provided in this guideline follow the listings inTables 1 and 2. The aim of grading the recommendations is to provide transparency between the underlyingevidence and the recommendation given.

1.2.2 Publication history

The EAU published a first guideline on bladder cancer in 2000. This document covered both superficial (non-muscle-invasive) bladder cancer and MIBC. As different treatment strategies are employed for these conditionsit was decided to split these topics up, resulting in a first publication of the MIBC guideline in 2004, withsubsequent updates in 2007, 2009 and this 2010 update. A quick reference document presenting the mainfindings is also available. All texts can be viewed and downloaded for personal use at the EAU website:http://www.uroweb.org/nc/professional-resources/guidelines/online/.

1.3 Summary of updated information

For all Sections, the literature has been assessed and the guideline updated whenever relevant information wasavailable. A proportion of non-muscle-invasive bladder cancers (NMIBC) presents with aggressive clinical

behaviour and are considered to be high-risk tumours. These tumours are discussed in this document as theirdiagnosis and treatment are very similar to those of MIBC (particularly Chapter 5).

Of note is the inclusion of: Gender- and race-related risk prognostic factors and upper urinary tract tumours (Chapter 2)

Radiological assessment (Diagnosis and Staging, Chapter 4)

Neo-adjuvant chemotherapy (Chapter 6)

Pre-treatment of patients prior to cystectomy (Chapter 9)

Minor additions to Chapter 10 (external beam radiotherapy and chemotherapy)

Metastatic disease, including a new section on bisphosphonates (Chapter 12) Stratification of recurrence and the inclusion of a follow-up schedule (Chapter 14).

1.4 Acknowledgements

The panel is grateful for the contribution of Prof. Dr. F. Algaba (urological pathologist) in assessing and revisingsection 3.2 concerning the histopathological grading of tumours. The support provided by research scientistDrs. J. Krabshuis has proved to be highly valuable in enhancing the methodological quality of this publication.

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Table 1: Level of evidence*.

Level Type of evidence

1a Evidence obtained from meta-analysis of randomised trials

1b Evidence obtained from at least one randomised trial

2a Evidence obtained from one well-designed controlled study without randomisation

2b Evidence obtained from at least one other type of well-designed quasi-experimental study3 Evidence obtained from well-designed non-experimental studies, such as comparative studies,

correlation studies and case reports

4 Evidence obtained from expert committee reports or opinions or clinical experience of respectedauthorities

Modified from Sackett et al. (1).

Table 2: Grade of recommendation*.

Grade Nature of recommendations

A Based on clinical studies of good quality and consistency addressing the specificrecommendations and including at least one randomised trial

B Based on well-conducted clinical studies, but without randomised clinical trialsC Made despite the absence of directly applicable clinical studies of good quality

*Modified from Sackett et al. (1).

1.5 Reference

1. Modified from Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Producedby Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, MartinDawes since November 1998.http://www.cebm.net/index.aspx?o=1025 [access date March 2010]

2. EPIDEMIOLOGY AND RISK FACTORS

2.1 Epidemiology

An estimated 104,400 incident cases of bladder cancer were diagnosed in Europe in 2006, of which 82,800were found in men and 21,600 in women. This represents 6.6% of the total cancers in men and 2.1% inwomen, with an estimated male:female ratio of 3.8:1.0. In men, bladder cancer was the fourth most commoncancer. Bladder cancer resulted in 4.1% of total cancer deaths in men and 1.8% of total cancer deaths inwomen (1). At the initial diagnosis of bladder cancer, 70% of cases are diagnosed as NMIBC and approximately30% as muscle-invasive disease. Among patients treated with radical cystectomy because of MIBC, 57% hadmuscle invasion at presentation, while 43% had been initially diagnosed with NMIBC that progressed despite

organ-preserving treatment (2). Approximately one-third of patients diagnosed with MIBC have undetectedmetastasis at the time of treatment of the primary tumour (3), while 25% of patients subjected to radicalcystectomy present with lymph node involvement at the time of surgery.

2.2 Risk factors for bladder cancer

2.2.1 Tobacco smoking

Tobacco smoking is the most well-established risk factor for bladder cancer, causing 50-65% of male casesand 20-30% of female cases. A casual relationship has been established between an exposure to tobaccoand cancer in studies in which chance, bias and confounding can be ruled out with reasonable confidence (4).The alleged carcinogenic constituents of tobacco smoke include arylamines, particularly the potent carcinogen4-aminobiphenyl (4-ABP), polycyclic aromatic hydrocarbons (PAHs), N-nitroso compounds, heterocyclicamines and various epoxides.

The incidence of bladder cancer is directly related to the duration of smoking and number ofcigarettes smoked per day (5). The risk of bladder cancer is also higher in those who start smoking at a youngage or who are exposed to environmental tobacco smoke during childhood (6). A recent meta-analysis lookedat 216 observational studies on cigarette smoking and cancer from 1961 to 2003, with reported estimates

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for current and/or former smokers. The pooled risk estimates for bladder cancer demonstrated a significantassociation for both current and former smokers. In an analysis of 21 studies, the overall relative risk calculatedfor current smokers was 2.77 (95% confidence interval [CI]: 2.17-3.54), while an analysis of 15 studies showedthat the overall relative risk calculated for former smokers was 1.72 (95% CI: 1.46-2.04) (7). An immediatedecrease in the risk of bladder cancer was observed in those who stopped smoking. The reduction was about40% within 1-4 years of quitting smoking and 60% after 25 years of cessation (5). The promotion of smokingcessation would result in the incidence of bladder cancer decreasing equally in men and women.

2.2.2 Occupational exposure to chemicals

Occupational exposure is the second most important risk factor for bladder cancer. Work-related casesaccounted for 20-25% of all bladder cancer cases in several series. The substances involved in chemicalexposure have been benzene derivatives and arylamines (2-naphthylamine, 4-ABP, 4,4-methylenedianilineand o-toluidine), and it is likely to occur in occupations in which dyes, rubbers, textiles, paints, leathers andchemicals are used (8). These chemicals have contributed minimally to the current incidence of bladder cancerin Western countries because of strict regulations. In fact, there has been a trend towards a decrease inbladder cancer due to occupational exposure, as indicated by a pooled analysis of 11 European case-controlstudies on bladder cancer between 1976 and 1996 (9).

An example of occupational exposure is that of aromatic amines. These established carcinogens forurothelium can be inactivated by a metabolic acetylation pathway. The presence of an NAT2 slow-acetylation

genotype has been associated with a higher risk of bladder cancer (10), suggesting that patients who are slowacetylators may be more susceptible to bladder cancer than rapid acetylators. Other risk factors include phenacetin, which was included in 1987 among proven human carcinogensby the International Agency for Research on Cancer (IARC). Some studies have suggested that the riskof bladder cancer due to phenacetin is dose dependent; however, the data concerning its metaboliteacetaminophen are controversial (11).

2.2.3 Radiation therapy

Increased rates of secondary bladder malignancies have been reported after external beam radiation therapy(EBRT) for gynaecological malignancies, with relative risks of 2 to 4 (12). A recent population cohort studyidentified 243,082 men treated for prostate cancer between 1988 and 2003 in the Surveillance, Epidemiologyand End Results database (SEER) in the USA. The standardised incidence ratios for bladder cancer developingafter radical prostatectomy (RP), EBRT, brachytherapy (BT) and EBRT-BT were 0.99, 1.42, 1.10 and 1.39,respectively, compared with the general US population. The increased risk of bladder cancer in patientsundergoing ERBT, BT or ERBT-BT should be taken into account during follow-up. As bladder cancer requires along time to develop, patients treated with radiation at a young age are at highest risk and should be followedup closely (13).

2.2.4 Dietary factors

Several dietary factors had been believed to be related to bladder cancer; however, a link remainscontroversial. Currently, there is limited evidence of a causal relationship between bladder cancer and dietaryfactors. A meta-analysis of 38 articles reporting data on diet and bladder cancer supported the hypothesis thatvegetable and fruit intake reduced the risk of bladder cancer (14).

2.2.5 Chronic urinary tract infection

Muscle-invasive bladder cancer, particularly invasive squamous cell carcinoma, is directly related to thepresence of chronic urinary tract infection.

2.2.6 Bladder schistosomiasis

Bladder schistosomiasis (bilharzia) has been considered a definitive cause of urinary bladder cancer with anassociated five-fold risk. Schistosomiasis is the second most common parasitic infection after malaria, withabout 600 million people exposed to infection in Africa, Asia, South America and the Caribbean (15). Althoughthere is a well-established relationship between squamous cell carcinoma of the bladder and schistosomiasis,the trends are changing for bladder cancer in endemic zones, such as Egypt. Data from the National CancerInstitute (NCI) Cairo, the largest tertiary cancer hospital in Egypt, showed that patients diagnosed in 2005 hada six-fold higher odds of developing transitional cell carcinoma compared with patients diagnosed in 1980 (16).The decline in the frequency of bladder cancer is related to a decline in the detection of bilharzia eggs in urine

samples, probably due to better control of the disease in rural populations (17).

2.2.7 Chemotherapy

The use of cyclophosphamide, an alkylating agent used for treatment of lymphoproliferative diseases and other

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non-neoplastic diseases, has been correlated with posterior development of muscle-invasive bladder cancer(MIBC) with a period of latency of 6-13 years. Acrolein is a metabolite of cyclophosphamide and is responsiblefor the increase in the incidence of bladder cancer. This effect occurs independently of the association ofhaemorrhagic cystitis with the same treatment (18,19).

2.2.8 Synchronous and metachronous upper urinary tract tumours

In some cases, there is an association between upper urinary tract tumours (UUTT) and bladder cancer. The

incidence of UUTT after diagnosis of NMIBC has been reported to be between 1.7% and 26%. Althoughsynchronous UUTT and NMIBC are uncommon, 46% are invasive.

In a retrospective review of 1,529 patients with primary superficial bladder carcinoma who underwent initialexamination of the upper urinary tract with excretory urography, those with a tumour in the bladder trigonewere almost 6 times more likely to develop a synchronous tumour in the upper urinary tract (20). Examinationof the upper urinary tract only in patients with a tumour in the trigone or with multiple bladder tumours coulddiagnose41% or 69% of UUTT, respectively.

In addition, the overall incidence of bladder cancer development after treatment of UUTT has been reportedin the literature as 15-50%. No level 1 evidence from prospective randomised trials was available. Intraluminaltumour seeding and pan-urothelial field change effects have both been proposed to explain intravesical

recurrences. In most cases, bladder cancer arises in the first 2 years after upper urinary tract-urothelial cellcarcinoma (UUT-UCC) management. However the risk is life-long and repeat episodes are common. Novariables can be used to predict future bladder cancer recurrence in UUT-UCC patients reliably. A history ofbladder cancer prior to UUT-UCC management and upper tract tumour multifocality are the only commonlyreported clinical risk factors in the current literature (21).

2.2.9 Gender

In a retrospective study of patients who underwent radical cystectomy, it was demonstrated that womenwere more likely to be diagnosed with primary muscle-invasive disease than men (85% vs 51%) (2). It hasbeen proposed that women are more likely to be older than men when diagnosed, with a direct effect on theirsurvival. In addition, delayed diagnosis is more likely in women after haematuria is observed, because thedifferential diagnosis in women includes diseases more prevalent than bladder cancer (22). Differences in the gender prevalence of bladder cancer may be due to other factors besides tobaccoand chemical exposure. In a large prospective cohort study, post-menopausal status was associated with an increase in

bladder cancer risk even after adjusting for smoking status. This result suggests that the differencesin oestrogen and androgen levels between men and women could be responsible for some of thedifference in the gender prevalence of bladder cancer (23).

An analysis of the 16 population-based registries included in the Surveillance Epidemiology and End

Results (SEER) database showed that 88% of all black and white patients in SEER were diagnosedwith bladder cancer between 1990 and 2003. On average, women were older than men within eachracial category at bladder cancer presentation (p < 0.001). They observed that an excess hazard ofdeath from bladder cancer was present during the first 2-3 years of follow-up among women, butafter adjustment for age and tumour characteristics this hazard was reduced to 30% among whitewomen. Thus, the authors proposed that significant differences in tumour characteristics and age

at presentation were not enough to explain the excess hazard of death from bladder cancer amongwomen. Other factors must also be investigated (24,25).

2.3 Conclusions about epidemiology and risk factors

Conclusion LE

The incidence of muscle-invasive disease has not changed for 5 years

Active and passive tobacco smoking continues to be the main risk factor, while exposure-relatedincidence is decreasing

2a

The increased risk of bladder cancer of patients submitted to EBRT, BT or a combination of EBRTand BT must be taken into account during patient follow-up. As bladder cancer requires time to

develop, patients treated with radiation at a young age are at the greatest risk and should be followedup closely

3

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The estimated male-to-female ratio for bladder cancer is 3.8:1.0. Women are more likely to bediagnosed with primary muscle-invasive disease than men

Currently, treatment decisions cannot be based on molecular markers

2.4 Recommendation for risk factors

Recommendation GR

The most important primary prevention measure for MIBC is to eliminate active and passive smoking B

2.5 References

1. Ferlay J, Autier P, Boniol M. Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence andmortality in Europe in 2006. Ann Oncol 2007 Mar;18(3):581-92.http://www.ncbi.nlm.nih.gov/pubmed/17287242

2. Vaidya A, Soloway MS, Hawke C, Tiguert R, Civantos F. De novo muscle invasive bladder cancer: isthere a change in trend? J Urol 2001 Jan;165(1):47-50.http://www.ncbi.nlm.nih.gov/pubmed/11125361

3. Prout GR Jr, Griffin PP, Shipley WU. Bladder carcinoma as a systemic disease. Cancer 1979 Jun;

43(6):2532-9.http://www.ncbi.nlm.nih.gov/pubmed/455239

4. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke andinvoluntary smoking. IARC Monogr Eval Carcinog Risks Hum 2004;83:1-1438.http://www.ncbi.nlm.nih.gov/pubmed/15285078

5. Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, Vineis P, Lopez-Abente G, Tzonou A, Chang-Claude J, Bolm-Audorff U, Jckel KH, Donato F, Serra C, Wahrendorf J, Hours M, TMannetje A,Kogevinas M, Boffetta P. Cigarette smoking and bladder cancer in men: a pooled analysis of 11casecontrol studies. Int J Cancer 2000 Apr;86(2):289-94.http://www.ncbi.nlm.nih.gov/pubmed/10738259

6. Bjerregaard BK, Raaschou-Nielsen O, Srensen M, Frederiksen K, Christensen J, Tjnneland A,Overvad K, Chapelon FC, Nagel G, Chang-Claude J, Bergmann MM, Boeing H, Trichopoulos D,Trichopoulou A, Oikonomou E, Berrino F, Palli D, Tumino R, Vineis P, Panico S, Peeters PH, Buenode-Mesquita HB, Kiemeney L, Gram IT, Braaten T, Lund E, Gonzalez CA, Berglund G, Allen N, Roddam A,Bingham S, Riboli E. Tobacco smoke and bladder cancerin the European Prospective Investigationinto Cancer and Nutrition. Int J Cancer 2006 Nov;119(10):2412-6.http://www.ncbi.nlm.nih.gov/pubmed/16894557

7. Gandini S, Botteri E, Iodice S, Boniol M, Lowenfels AB, Maisonneuve P, Boyle P. Tobacco smokingand cancer: a meta-analysis. Int J Cancer 2008 Jan;122(1):155-64.http://www.ncbi.nlm.nih.gov/pubmed/17893872

8. Pashos CL, Botteman MF, Laskin BL, Redaelli A. Bladder cancer: epidemiology, diagnosis, andmanagement. Cancer Pract 2002 Nov-Dec;10(6):311-22.http://www.ncbi.nlm.nih.gov/pubmed/12406054

9. Kogevinas M, tMannetje A, Cordier S, Ranft U, Gonzlez CA, Vineis P, Chang-Claude J, Lynge E,Wahrendorf J, Tzonou A, Jckel KH, Serra C, Porru S, Hours M, Greiser E, Boffetta P. Occupation and

bladder cancer among men in Western Europe. Cancer Causes and Control 2003 Dec;14(10):907-14.http://www.ncbi.nlm.nih.gov/pubmed/14750529

10. Garca-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein DW, Tardn A, Serra C,Carrato A, Garca-Closas R, Lloreta J, Castao-Vinyals G, Yeager M, Welch R, Chanock S, ChatterjeeN, Wacholder S, Samanic C, Tor M, Fernndez F, Real FX, Rothman N. NAT2 slow acetylation,GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study andmeta-analyses. Lancet 2005 Aug;366(9486):649-59.http://www.ncbi.nlm.nih.gov/pubmed/16112301

11. Castelao JE, Yuan JM, Gago-Dominguez M, Yu MC, Ross RK. Non-steroidal anti-inflammatory drugsand bladder cancer prevention. Br J Cancer 2000 Apr;82(7):1364-9.http://www.ncbi.nlm.nih.gov/pubmed/10755416

12. Chrouser K, Leibovich B, Bergstralh E, Zincke H, Blute M. Bladder cancer risk following primary and

adjuvant external beam radiation for prostate cancer. J Urol 2006 Jul;174(1):107-10.http://www.ncbi.nlm.nih.gov/pubmed/15947588

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13. Nieder AM, Porter MP, Soloway MS. Radiation therapy for prostate cancer increases subsequentrisk of bladder and rectal cancer: a population based cohort study. J Urol 2008 Nov;180(5):2005-9;discussion 2009-10.http://www.ncbi.nlm.nih.gov/pubmed/18801517

14. Steinmaus CM, Nuez S, Smith AH. Diet and bladder cancer: a meta-analysis of six dietary variables.Am J Epidemiol 2000 Apr;151(7):693-702.http://www.ncbi.nlm.nih.gov/pubmed/10752797

15. [No authors listed.] Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on theEvaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June, 1994. IARC Monogr Eval CarcinogRisks Hum 1994;61:1-241.http://www.ncbi.nlm.nih.gov/pubmed/7715068

16. Felix AS, Soliman AS, Khaled H, Zaghloul MS, Banerjee M, El-Baradie M, El-Kalawy M, Abd-ElsayedAA, Ismail K, Hablas A, Seifeldin IA, Ramadan M, Wilson ML. The changing patterns of bladder cancerin Egypt over the past 26 years. Cancer Causes Control 2008 May;19(4):421-9.http://www.ncbi.nlm.nih.gov/pubmed/18188671

17. Gouda I, Mokhtar N, Bilal D, El-Bolkainy T, El-Bolkainy NM. Bilharziasis and bladder cancer: a timetrend analysis of 9843 patients. J Egypt Natl Canc Inst 2007 Jun;19(2):158-62.http://www.ncbi.nlm.nih.gov/pubmed/19034337

18. Kaldor JM, Day NE, Kittelmann B, Pettersson F, Langmark F, Pedersen D, Prior P, Neal F, Karjalainen

S, Bell J et al. Bladder tumours following chemotherapy and radiotherapy for ovarian cancer: a case-control study. Int J Cancer 1995 Sept 27;63(1):1-6.http://www.ncbi.nlm.nih.gov/pubmed/7558434

19. Travis LB, Curtis RE, Glimelius B, Holowaty EJ, Van Leeuwen FE, Lynch CF, Hagenbeek A, Stovall M,Banks PM, Adami J, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkins lymphoma. J Natl Cancer Inst 1995 Apr;87(7):524-30.http://www.ncbi.nlm.nih.gov/pubmed/7707439

20. Palou J, Rodrguez-Rubio F, Huguet J, Segarra J, Ribal MJ, Alcaraz A, Villavicencio H. Multivariateanalysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinarytract tumor. J Urol 2005 Sep;174(3):859-61; discussion 861.http://www.ncbi.nlm.nih.gov/pubmed/16093970

21. Azmar MD, Comperat E, Richard F, Cussenot O, Rouprt M. Bladder recurrence after surgery forupper urinary tract urothelial cell carcinoma: frequency, risk factors, and surveillance.Urol Oncol 2009Sep 15. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/pubmed/19762256

22. Crdenas-Turanzas M, Cooksley C, Pettaway CA, Sabichi A, Grossman HB, Elting L. Comparativeoutcomes of bladder cancer. Obstet Gynecol 2006 Jul;108(1):169-75.http://www.ncbi.nlm.nih.gov/pubmed/16816072

23. McGrath M, Michaud DS, De Vivo I. Hormonal and reproductive factors and the risk of bladder cancerin women. Am J Epidemiol 2006 Feb;163(3):236-44.http://www.ncbi.nlm.nih.gov/pubmed/16319290

24. Scosyrev E, Noyes K, Feng C, Messing E. Sex and racial differences in bladder cancer presentationand mortality in the US. Cancer 2009 Jan;115(1):68-74.http://www.ncbi.nlm.nih.gov/pubmed/19072984

25. Stenzl A. Words of Wisdom. Re: Sex and racial differences in bladder cancer presentation and

mortality in the US. Eur Urol 2010 April;57(4):729.

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3. CLASSIFICATION

3.1 Tumour, Nodes, Metastases classification

The Tumour, Nodes, Metastases (TNM) Classification of Malignant Tumours is the method most widely used toclassify the extent of cancer spread. Recently a seventh edition was published, effective as of 2010 (1). Thereare no significant modifications to this for bladder cancer compared with the previous (2002) edition.

Table 2: 2009 TNM classification of urinary bladder cancer.

T - Primary tumour

TX Primary tumour cannot be assessedT0 No evidence of primary tumourTa Non-invasive papillary carcinomaTis Carcinomain situ: flat tumourT1 Tumour invades subepithelial connective tissueT2 Tumour invades muscle T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half)T3 Tumour invades perivesical tissue

T3a Microscopically T3b Macroscopically (extravesical mass)T4 Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate, uterus or vagina T4b Tumour invades pelvic wall or abdominal wall

N - Lymph nodes

NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac or presacral)N2 Metastasis in multiple lymph nodes in the true pelvis (hypogastric, obturator, external iliac or presacral)N3 Metastasis in a common iliac lymph node(s)

M - Distant metastasis

M0 No distant metastasisM1 Distant metastasis

3.2 Histological grading of non-muscle-invasive bladder tumours

In 1998, a new classification of non-invasive urothelial tumours was proposed by the World HealthOrganization (WHO) and the International Society of Urological Pathology (ISUP). It was published by the WHOin 2004 (2,3) (Table 3). Its major contribution is a detailed histological description of the various grades usingspecific cytological and architectural criteria. A website (http://www.pathology.jhu.edu/bladder) illustratingexamples of various grades was developed to improve accuracy in using the system.

Table 3: WHO grading in 1973 and 2004 (2,3).

1973 WHO grading

Urothelial papilloma

Grade 1: well differentiated

Grade 2: moderately differentiated

Grade 3: poorly differentiated

2004 WHO grading

Urothelial papilloma

Papillary urothelial neoplasm of low malignant potential (PUNLMP)

Low-grade papillary urothelial carcinoma

High-grade papillary urothelial carcinoma

3.2.1 WHO grading

The 2004 WHO grading differentiates between papilloma, papillary urothelial neoplasms of low malignant

potential (PUNLMP) and low-grade and high-grade urothelial carcinomas. The papilloma is composed of a delicate fibrovascular core covered by normal urothelium. A PUNLMPis defined as a papillary fibrovascular growth covered by proliferated urothelium exceeding the normalthickness. Although PUNLMPs have a negligible risk of progression, they are not completely benign and have

UPDATE APRIL 2010 11


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a tendency to recur. The low-grade papillary urothelial carcinoma group includes all former grade 1 (WHO1973) cases and some former grade 2 cases (if a variation of architectural and cytological features exist at highmagnification). Use of the 2004 WHO classification is recommended as this should result in a uniform diagnosisof tumours better classified according to risk potential. However, until the 2004 WHO classification hasbeen validated by more clinical trials, tumours should be graded using both the 1973 and the 2004 WHOclassifications (4).

Most clinical trials published so far on bladder tumours have been performed using the 1973 WHOclassification, so this is used in the 2010 edition of the guidelines.

3.3 Pathology

3.3.1 Urologist handling of specimens

In transurethral resection (TUR) specimens, the superficial and deep areas of the tumour must be sent to thepathology laboratory separately. If random biopsies of the flat mucosa have been carried out, each biopsy ofthe flat mucosa must also be sent separately. In radical cystectomy the bladder fixation must be carried out as soon as possible. The pathologistmust open the specimen from the urethra to the bladder dome and fix the specimen in formalin. In somecircumstances this procedure can also be performed by the urologist. In a female cystectomy specimen,the length of the urethral segment removed en bloc with the specimen should be checked, preferably by the

urological surgeon (5).

3.3.2 Pathologist handling of specimens

Specimen handling should follow the general rules as published by a collaborative group of pathologists andurologists (6). It must be stressed that it may be very difficult to confirm the presence of a neoplastic lesionusing gross examination of the cystectomy specimen after TUR or chemotherapy, so the entire retracted orulcerated area must be included. It is compulsory to study the urethra, the ureter, the prostate in men and the radial margins (7). Inurethra-sparing cystectomy, the level of urethral dissection, completeness of the prostate specifically at theapex (in men), and the inclusion of the entire bladder neck and amount of adjacent urethra (in women) shouldbe documented.

3.3.3 Pathology of muscle-invasive bladder cancer

In invasive bladder cancer there are usually no cases of PUNLMP and low-grade carcinoma. All cases are high-grade urothelial carcinomas (grade II or grade III in WHO 1973). For this reason, no more prognostic informationcan be provided by grading muscle-invasive bladder cancer (8). However, some morphological subtypes canbe important for helping with prognosis and treatment decisions: small-cell carcinomas

urothelial carcinomas with squamous and/or glandular partial differentiation

spindle cell carcinomas

some urothelial carcinomas with trophoblastic differentiation

micropapillary urothelial carcinoma

nested carcinoma.

For staging, TNM 2002/2009 (6thor 7thedition) is recommended. The pattern of muscular invasion can provide

some prognostic information. Most cases show nodular or cordonal growth, but about 44% have an infiltrativepattern. According to some authors (8), the median survival time of a patient with an infiltrative pattern is lowerthan that for an individual with other pattern types (p = 0.06). Blood vessel invasion and lymph node infiltrationhave an independent prognostic significance (9). It seems that the pN category is closely related to the numberof lymph nodes studied by the pathologist. For this reason, some authors have observed that more than ninelymph nodes have to be investigated to reflect pN0 appropriately (10). New prognostic markers are under study (11). Currently, insufficient evidence exists to recommendthe standard use of the prognostic marker p53 in high-risk muscle-invasive disease, as it will not yield sufficientdata upon which to base treatment in an individual patient.



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3.3.4 Recommendations for the assessment of tumour specimens

Recommendations for assessment of tumour specimens

Mandatory evaluations

Depth of invasion (categories pT2 vs pT3a, pT3b or pT4)

Margins with special attention paid to the radial margin

Histological subtype, if it has clinical implications

Extensive lymph node representation (more than nine)

Optional evaluations

Bladder wall blood vessel invasion

Pattern of muscle invasion

3.4 References

1. Sobin LH, Gospodariwicz M, Wittekind C (eds). TNM classification of malignant tumors. UICCInternational Union Against Cancer. 7th edn. Wiley-Blackwell, 2009 Dec; pp. 262-265.http://cancerstaging.blogspot.com/2005/02/urinary-bladder.html

2. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society ofUrological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinarybladder. Am J Surg Pathol 1998 Dec;22(12):1435-48.http://www.ncbi.nlm.nih.gov/pubmed/9850170

3. Sauter G, Algaba F, Amin M, Busch C, Cheville J, Gasser T, Grignon DJ, Hofstadter F, Lopez-BeltranA, Epstein JI. Tumours of the urinary system: non-invasive urothelial neoplasias. In: Eble JN, Sauter G,Epstein Jl, Sesterhenn I, eds. WHO classification of classification of tumors of the urinary system andmale genital organs. Lyon: IARCC Press, 2004, pp. 29-34.

4. Lopez-Beltran A, Montironi R. Non-invasive urothelial neoplasms: according to the most recent WHOclassification. Eur Urol 2004 Aug;46(2):170-6.http://www.ncbi.nlm.nih.gov/pubmed/15245809

5. Stenzl A. Current Concepts for Urinary Diversion in Women. Eur Urol (EAU Update Series 1);2003:91-9.

6. Lopez-Beltran A, Bassi PF, Pavone-Macaluso M, Montironi R, European Society of Uropathology;Uropathology Working Group. Handling and pathology reporting of specimens with carcinoma of theurinary bladder, ureter, and renal pelvis. A joint proposal of the European Society of Uropathology andthe Uropathology Working Group. Vichows Arch 2004 Aug;445(2):103-10.http://www.ncbi.nlm.nih.gov/pubmed/15185074

7. Herr HW. Pathologic evaluation of radical cystectomy specimens. Cancer 2002;95(3):668-9.http://www.ncbi.nlm.nih.gov/pubmed/12209761

8. Jimenez RE, Gheiler E, Oskanian P, Tiguert R, Sakr W, Wood DP Jr, Pontes JE, Grignon DJ. Gradingthe invasive component of urothelial carcinoma of the bladder and its relationship with progression-free survival. Am J Surg Pathol 2000 Jul;24(7):980-7.http://www.ncbi.nlm.nih.gov/pubmed/10895820

9. Leissner J, Koeppen C, Wolf HK. Prognostic significance of vascular and perineural invasion in

urothelial bladder cancer treated with radical cystectomy. J Urol 2003 Mar;169:955-60.http://www.ncbi.nlm.nih.gov/pubmed/12576821

10. Shariat SF, Karam JA, Lerner SP. Molecular markers in bladder cancer. Curr Opin Urol 2008 Jan;18(1):1-8.http://www.ncbi.nlm.nih.gov/pubmed/18090481

11. Tiguert R, Lessard A, So A, Fradet Y. Prognostic markers in muscle invasive bladder cancer. World JUrol 2002 Aug;20:190-5.http://www.ncbi.nlm.nih.gov/pubmed/12196903



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4. DIAGNOSIS AND STAGING

4.1 Diagnosis

4.1.1 Symptoms

Painless haematuria is a common finding. In addition, some patients complain of urgency, dysuria, increasedfrequency and pelvic pain. Pelvic pain and all the symptoms related to urinary tract obstruction are found inmore advanced tumours.

4.1.2 Physical examination

Physical examination should include rectal and vaginal bimanual palpation. A palpable pelvic mass can befound in patients with locally advanced tumours. In addition, bimanual examination should be carried outbefore and after TUR to assess whether there is a palpable mass or if the tumour is fixed to the pelvic wall (1,2).

4.1.3 Imaging

4.1.3.1 CT imagingMultidetector-row computed tomography (CT) urography is the preferred imaging modality for the diagnosisand staging of upper urinary tract and bladder cancer (3). CT urography has a higher diagnosis accuracy forurothelial cancers than intravenous urography (IVU) (level of evidence: 2b), but has the disadvantage of higherradiation exposure.

4.1.3.2 Intravenous urography (IVU)Intravenous urography is used primarily to detect filling defects in the calices, renal pelvis and ureters, andhydronephrosis, which may indicate the presence of a ureteral tumour. IVU may also detect large tumours,which may be seen as filling defects in the bladder. The need to perform routine IVU once a bladder tumourhas been detected is now questioned because of the low incidence of significant findings obtained with thismethod (4-6) (level of evidence: 3). The incidence of UUTT is low (1.8%), but this increases to 7.5% in tumourslocated in the trigone (5).

4.1.3.3 UltrasonographyTransabdominal ultrasonography allows characterisation of large renal masses, detection of hydronephrosisand visualisation of intraluminal filling defects in the bladder. It assists with diagnosis of stones when combinedwith an abdominal X-ray (level of evidence: 3) (1,2).

4.1.3.4 Recommendations for staging in verified bladder tumours

Recommendation GR

Diagnosis of invasive bladder cancer Cystoscopy and biopsy

Imaging only if staging will make a difference to the selection of treatment options

Local staging for patients considered suitable for radical treatment Magnetic resonance imaging with fast dynamic contrast enhancement

Multidetector-row CT with contrast enhancement

B

For patients with confirmed muscle-invasive bladder cancer

Multidetector-row CT of the chest, abdomen and pelvis, including multidetector-row CTurography for complete examination of the upper urinary tracts

Lesser alternatives (e.g. if multidetector-row CT is unavailable) are excretory urography and

a chest X-ray

B

4.1.4 Urinary cytology and urinary markers

Examination of a voided urine or bladder-washing specimen for exfoliated cancer cells has high sensitivity inhigh-grade tumours (level of evidence: 3). It is therefore useful when a high-grade malignancy or carcinomainsitu(CIS) is present. Positive urinary cytology may indicate a urothelial tumour anywhere in the urinary tract from the calix,through the ureters, into the bladder and proximal urethra. Cytological interpretation is user dependent(7). The evaluation can be hampered by low cellular yield, urinary tract infections, stones or intravesical

instillations. In experienced hands, however, specificity exceeds 90% (8) (level of evidence: 2b). Cytologyshould be performed on fresh urine with adequate fixation. Morning urine is not suitable as cytolysis may oftenbe present. No urinary marker is registered specifically for the diagnosis of invasive bladder cancer.However, as most invasive tumours are of high grade the positive predictive value of markers may be greater(9).



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4.1.5 Cystoscopy

The diagnosis of bladder cancer ultimately depends on cystoscopic examination of the bladder and histologicalevaluation of the resected tissue. In general, cystoscopy is initially performed in the office, using flexibleinstruments. If a bladder tumour has been visualised unequivocally in earlier imaging studies, such as CT,magnetic resonance imaging or ultrasonography, a diagnostic cystoscopy may be omitted as the patient willundergo TUR for a histological diagnosis. A careful description of the finding is necessary. It should include documentation of the site, size,

number and appearance (papillary or solid) of the tumours as well as a description of mucosal abnormalities.Use of a bladder diagram is recommended.

4.1.6 Transurethral resection (TUR) of invasive bladder tumours

The goal of TUR is to enable a correct diagnosis by the pathologist, which means including bladder muscle inthe adequately sized resection biopsies. The strategy of resection depends on the size of the lesion. Small tumours (less than 1 cm) can beresected en bloc, where the specimen contains the complete tumour plus a part of the underlying bladderwall including bladder muscle. Larger tumours have to be resected separately in fractions, which includethe exophytic part of the tumour, the underlying bladder wall with the detrusor muscle and the edges ofthe resection area. The specimens from different fractions must be referred to the pathologist in separatecontainers to enable him to make a correct diagnosis. Cauterisation has to be avoided as much as possible

during the resection to prevent tissue destruction.

4.1.7 Random bladder and (prostatic) urethral biopsy

Bladder tumours are often multifocal. Moreover tumours can be accompanied by CIS or dysplasia. Theselesions may present themselves as velvet-like, reddish areas, indistinguishable from inflammation, or may benot visible at all. The biopsies from normal-looking mucosa in patients with bladder tumours, so-called randombiopsies (R-biopsies) or selected site mucosal biopsies, are only recommended if fluorescent areas are seenwith photodynamic diagnosis (PDD). Fluorescence cystoscopy is performed using filtered blue light afterintravesical instillation of a photosensitiser, usually 5-aminolevulinic acid (5-ALA) or hexaminolaevulinate (HAL).It has been confirmed that fluorescence-guided biopsy and resection are more sensitive than conventionalprocedures in detecting malignant tumours, particularly CIS (10-12) (level of evidence: 2a). However, false-positive results may be induced by inflammation, recent TUR or intravesical instillation therapy. Materialobtained by random or directed biopsies must be sent for pathological assessment in separate containers.

The involvement of the prostatic urethra and ducts in male patients with bladder tumours has beenreported. Although the exact risk is not known, it seems to be higher if tumour is located on the trigone orbladder neck, in the presence of bladder CIS and in multiple tumours (13,14) (level of evidence: 3). In thesecases and when cytology is positive or when abnormalities of prostatic urethra are visible, biopsies of theprostatic urethra are recommended. The biopsy is taken using resection loop from the precolicular area.Special care must be taken with tumours at the bladder neck and trigone in female patients where urethralpreservation in subsequent orthotopic neobladder is planned. Preoperative bladder neck biopsies areadvisable but not mandatory, provided frozen section at the urethral margin is taken at the time of surgery(level of evidence 4).

4.1.8 Second resection

There is a significant risk of residual tumour after the initial TUR (15,16) (level of evidence: 1). Persistent diseasewas observed in 33-53% of patients (16-22). Moreover, the tumour may be understaged by the initial resection.There is a 10% probability that tumours initially staged as being of a lower stage are in fact muscle-invasive(17,18). Correct staging is extremely important since it will directly affect the treatment modality. A second TURshould always be performed when the initial resection has been incomplete, e.g. when multiple and/or largetumours are present, or when the pathologist has reported that the specimen contained no muscle tissue.Furthermore, a second TUR should be performed when a high-grade, non-muscle-invasive tumour or a T1tumour has been detected at the initial TUR. There is no consensus about the strategy and timing of a secondTUR. Most authors recommend resection at 2-6 weeks after the initial TUR. The procedure should include aresection of the primary tumour site.

4.1.9 Concomitant prostate cancer

Ruling out progressive prostate cancer should be considered since 25-46% of patients submitted tocystectomy for bladder cancer (23,24) appear to have prostate cancer on final pathology. Unless the entireprostate is to be removed during cystectomy, any type of prostate cancer should be excluded.



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4.1.10 Recommendations for primary assessment of presumably invasive bladder tumours

Recommendation GR

Renal and bladder ultrasonography, IVU or CT prior to TUR B

Cystoscopy with description of the tumour (site, size, number and appearance) and mucosalabnormalities. A bladder diagram is recommended

C

TUR in one piece for small tumours (< 1 cm), plus a deep resection with part from the underlyingbladder muscle

B

TUR in fractions (including muscle tissue) for larger tumours B

Biopsies of abnormal-looking urotheliumBiopsies from normal-looking mucosa when cytology is positive or when exophytic tumour is of non-papillary appearance or in case of fluorescence if PDD is used

C

Biopsy of the prostatic urethra in the case of bladder neck tumour, when bladder CIS is present orsuspected or when abnormalities of prostatic urethra are visible

C

Careful inspection with histological evaluation of the bladder neck and urethral margin, either prior toor at the time of cystoscopy in women undergoing a subsequent orthotopic neobladder

C

A second TUR at 2-6 weeks after the initial resection when it was incomplete or when a high-grade or

T1 tumour was detected

B

The pathological report should specify the grade, the depth of tumour invasion and whether thelamina propria and muscle are present in the specimen

C

4.2 Imaging for staging in verified bladder tumours

Imaging is indicated only if there is a clinical consequence. The treatment and prognosis for invasive bladdercancer is determined by tumour stage and grade (25). Tumour staging must be accurate for selecting thecorrect treatment in clinical practice. The use of CT and MR imaging has largely replaced other imagingmodalities for staging of invasive bladder cancer.

The purpose of imaging for staging invasive bladder cancer is to: Assess the extent of local tumour invasion

Detect tumour spread to lymph nodes

Detect tumour spread to other distant organs (liver, lung, bones, peritoneum, pleura, kidney, adrenal

gland and others).

4.2.1 Local staging of invasive bladder cancer

Both CT and MR imaging may be used for assessment of local invasion (26) but they are unable to detectmicroscopic invasion of perivesical fat (T3a) (27). The aim of CT and MR imaging is therefore to detect T3bdisease or higher.

4.2.1.1 MR imaging for local staging of invasive bladder cancer

MR imaging has superior soft tissue contrast resolution compared with CT, but poorer spatial resolution.In studies performed before the availability of multidetector-row CT (MDCT), MR imaging was reported to be

more accurate for local assessment. The accuracy of MR imaging for primary tumour staging varies from 73%to 96% (mean 85%). These values were 10-33% (mean 19%) higher than those obtained with CT (28). Fast dynamic contrast-enhanced MR imaging helps to differentiate bladder tumour fromsurrounding tissues because enhancement of the tumour occurs earlier than the normal bladder wall due toneovascularisation (29,30). Fast dynamic MR imaging with images acquired at one image per second helps todistinguish tumour from postbiopsy reaction (29).

In 2006 a link was established between gadolinium-based contrast agents (Gd-CA) and nephrogenic systemicfibrosis (NSF) which may result in a fatal or debilitating systemic fibrosis. It is widely accepted that patients withreduced (eGFR < 60 ml/min) or severely reduced (eGFR < 30 ml/min) renal function are at risk of developingNSF and in such patients the use of non-ionic linear Gd-CAs should be avoided (gadodiamide, gadopentetatedimeglumine and gadoversetamide). Some centres advocate the use of stable macrocyclic contrast agents

(gadobutrol, gadoterate meglumine or gadoteridol) in these circumstances whilst others suggest usingiodinated contrast media and performing contrast enhanced CT (31) (level of evidence 4).



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4.2.1.2 CT imaging for local staging of invasive bladder cancer

The advantages of CT include shorter acquisition time, wider coverage in a single breath hold, and lowersusceptibility to various patient factors. CT imaging is unable to differentiate between stages Ta to T3a, but it is useful clinically for detectinginvasion into the perivesical fat (T3b) and adjacent organs. The accuracy of CT in determining extravesicaltumour extension varies from 55% to 92% (32) and increases with more advanced disease (33). A study by Kim et al. to determine the accuracy of MDCT for detection and staging of bladder cancer

showed that CT had lower sensitivity (89%) and higher specificity (95%) compared to MR imaging for diagnosisof perivesical invasion, while the cancer detection rate and overall accuracy for perivesical invasion were similar(34). These findings are explained by better visualisation of perivesical fat invasion on MR imaging, but becauseonly mild inflammation around bladder cancers mimics perivesical invasion, this results in overstaging with MRimaging.

4.2.2 Imaging of nodal involvement

The assessment of nodal status based simply on size is limited by the inability of both CT and MR imagingto identify metastases in normal sized or minimally enlarged nodes. Sensitivities for detection of lymph nodemetastases are low, ranging from 48% to 87%. Specificities are also low as nodal enlargement may be dueto benign pathology. Overall, the results of CT and MR imaging for detection of lymph node metastases in avariety of primary pelvic tumours are similar (35-39). Pelvic nodes greater than 8 mm and abdominal nodes

greater than 10 mm in maximum short axis diameter (MSAD) should be regarded as enlarged on CT and MRimaging (40,41).

Currently there is no evidence for routine use of PET CT in nodal staging of BC, although the method has beenevaluated with varying results in small prospective trials (42,43).

4.2.3 Extravesical urothelial carcinoma

Multidetector-row CT urography is the technique of choice for diagnosing upper urinary tract urothelialcancer (44,45). MDCT urography should be incorporated into the CT staging protocol to rule out extravesicalcarcinoma.

4.2.4 Distant metastases other than lymph nodes

Prior to any treatment aimed at cure, it is essential to evaluate the presence of distant metastases. MDCT andMR imaging are the diagnostic tools of choice to detect metastases to lung and liver. Metastases to bones orbrain at presentation of invasive bladder cancer are rare. Bone scan and additional brain imaging are thereforenot routinely indicated unless the patient has specific symptoms or signs to suggest bone or brain metastases(46,47). MR imaging is more sensitive and specific for diagnosing bone metastases than bone scintigraphy(48,49) (level of evidence: 2b).

4.2.5 Conclusions for staging of verified bladder tumour

Conclusion LE

Diagnosis of invasive bladder cancer is made by cystoscopy and biopsy

Imaging is used for formal staging only if it will make a difference to the selection of treatment options

In all T1 tumours considered for conservative treatment, a second TUR is recommended beforedeciding on definite treatment

Deciding on definite treatment

MRI is the preferred modality if the patient is evaluated for radical treatment. MDCT due to its higherspecificity may be equivalent to MRI regarding local staging

CT is recommended if there is suspicion of locally advanced or metastatic disease precluding radicaltreatment

2b-3

4.2.6 Recommendations for staging of verified bladder tumour

Recommendation GR

For optimal local staging, either MR imaging with fast dynamic contrast-enhancement or MDCT withcontrast enhancement are recommended for patients considered suitable for radical treatment

B



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For patients with confirmed muscle-invasive bladder cancer, MDCT of the chest, abdomen and pelvisis the optimal form of staging, including MDCT urography for complete examination of the upperurinary tracts. If MDCT is not available, lesser alternatives are excretory urography and a chest X-ray

B

4.3 References

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Jan;67(1):54-60.http://www.ncbi.nlm.nih.gov/pubmed/1993277

2. Wijkstrm H, Norming U, Lagerkvist M, Nilsson B, Nslund I, Wiklund P. Evaluation of clinical stagingbefore cystectomy in transitional cell bladder carcinoma: a long-term follow-up of 276 consecutivepatients. Br J Urol 1998 May;81(5):686-91.http://www.ncbi.nlm.nih.gov/pubmed/9634042

3. Van Der Molen AJ, Cowan NC, Mueller-Lisse UG, Nolte-Ernsting CC, Takahashi S, Cohan RH. CTurography: definition, indications and techniques. A guideline for clinical practice. Eur Radiol 2008Jan;18(1):4-17.http://www.ncbi.nlm.nih.gov/pubmed/17973110

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http://www.ncbi.nlm.nih.gov/pubmed/89963385. Palou J, Rodriguez-Rubio F, Huguet J, Segarra J, Ribal MJ, Alcaraz A, Villavicencio H. Multivariate

analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinarytract tumor. J Urol 2005 Sep;174(3):859-61.http://www.ncbi.nlm.nih.gov/pubmed/16093970

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7. Raitanen M-P, Aine R, Rintala E, Kallio J, Rajala P, Juusela H, Tammela TL; FinnBladder Group.Differences between local and review urinary cytology and diagnosis of bladder cancer. Aninterobserver multicenter analysis. Eur Urol 2002 Mar;41(3):284-9.http://www.ncbi.nlm.nih.gov/pubmed/12180229

8. Lokeshwar VB, Habuchi T, Grossman HB, Murphy WM, Hautmann SH, Hemstreet GP 3rd, Bono AV,Getzenberg RH, Goebell P, Schmitz-Drger BJ, Schalken JA, Fradet Y, Marberger M, Messing E,Droller MJ. Bladder tumor markers beyond cytology: international consensus panel on bladder tumormarkers. Urology 2005 Dec;66 (6 Suppl 1):35-63.http://www.ncbi.nlm.nih.gov/pubmed/16399415

9. Van Rhijn BW, van der Poel HG, van der Kwast Th. Urine Markers for bladder cancer surveillance: asystematic review. Eur Urol 2005 Jun;47(6):736-48http://www.ncbi.nlm.nih.gov/pubmed/15925067

10. Schmidbauer J, Witjes F, Schmeller N, Donat R, Susani M, Marberger M; Hexvix PCB301/01 StudyGroup. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescencecystoscopy. J Urol 2004 Jan;171(1):135-8.http://www.ncbi.nlm.nih.gov/pubmed/14665861

11. Jichlinski P, Guillou L, Karlsen SJ, Malmstrm PU, Jocham D, Brennhovd B, Johansson E, Grtner

T, Lange N, van den Bergh H, Leisinger HJ. Hexyl aminolevulinate fluorescence cystoscopy: newdiagnostic tool for photodiagnosis of superficial bladder cancera multicenter study. J Urol 2003Jul;170(1):226-9.http://www.ncbi.nlm.nih.gov/pubmed/12796694

12. Hungerhuber E, Stepp H, Kriegmair M, Stief Ch, Hofstetter A, Hartmann A, Knuechel R, Karl A,Tritschler S, Zaak D. Seven years experience with 5-aminolevulinic acid in detection of transitional cellcarcinoma of the bladder. Urology 2007 Feb;69(2):260-4.http://www.ncbi.nlm.nih.gov/pubmed/17320660

13. Matzkin H, Soloway MS, Hardeman S. Transitional cell carcinoma of the prostate. J Urol 1991Nov;146(5):1207-12.http://www.ncbi.nlm.nih.gov/pubmed/1942262

14. Mungan MU, Canda AE, Tuzel E, Yorukoglu K, Kirkali Z. Risk factors for mucosal prostatic urethral

involvement in superficial transitional cell carcinoma of the bladder. Eur Urol 2005 Nov;48(5):760-3.http://www.ncbi.nlm.nih.gov/pubmed/16005563



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15. Brausi M, Collette L, Kurth K, van der Meijden A, Oosterlinck W, Witjes JA, Newling D, Bouffioux C,Sylvester RJ; EORTC Genito-Urinary Tract Cancer Collaborative Group. Variability in the recurrencerate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: acombined analysis of seven EORTC studies. Eur Urol 2002 May;41(5):523-31.http://www.ncbi.nlm.nih.gov/pubmed/12074794

16. Miladi M, Peyromaure M, Zerbib M, Saghi D, Debr B. The value of a second transurethral resectionin evaluating patients with bladder tumours. Eur Urol 2003 Mar;43(3):241-5.

http://www.ncbi.nlm.nih.gov/pubmed/1260042617. Jakse G, Algaba F, Malmstrm PU, Oosterlinck W. A second-look TUR in T1 transitional cell

carcinoma: why? Eur Urol 2004 May;45(5):539-46.http://www.ncbi.nlm.nih.gov/pubmed/15082193

18. Brauers A, Buettner R, Jakse G. Second resection and prognosis of primary high risk superficialbladder cancer: is cystectomy often too early? J Urol 2001 Mar;165(3):808-10.http://www.ncbi.nlm.nih.gov/pubmed/11176474

19. Schips L, Augustin H, Zigeuner RE, Gall G, Habermann H, Trummer H, Pummer K, Hubmer G. Isrepeated transurethral resection justified in patients with newly diagnosed superficial bladder cancer?Urology 2002 Feb;59(2):220-3.http://www.ncbi.nlm.nih.gov/pubmed/11834389

20. Grimm MO, Steinhoff Ch, Simon X, Spiegelhalder P, Ackermann R, Vgeli, TA. Effect of routine repeat

transurethral resection for superficial bladder cancer: a long-term observational study. J Urol 2003Aug;170(2 Pt 1):433-7.http://www.ncbi.nlm.nih.gov/pubmed/12853793

21. Divrik RT, Yildirim , Zorlu F, Ozen H. The effect of repeat transurethral resection on recurrence andprogression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: aprospective, randomized clinical trial. J Urol 2006 May;175(5):1641-4.http://www.ncbi.nlm.nih.gov/pubmed/16600720

22. Jahnson S, Wiklund F, Duchek M, Mestad O, Rintala E, Hellsten S, Malmstrm PU. Results ofsecondlook resection after primary resection of T1 tumour of the urinary bladder. Scand J UrolNephrol 2005;39(3):206-10.http://www.ncbi.nlm.nih.gov/pubmed/16127800

23. Damiano R, Di Lorenzo G, Cantiello F, De Sio M, Perdon S, DArmiento M, Autorino R.Clinicopathologic features of prostate adenocarcinoma incidentally discovered at the time of radicalcystectomy: an evidence-based analysis. Eur Urol 2007 Sep;52(3):648-57.http://www.ncbi.nlm.nih.gov/pubmed/17600614

24. Gakis G, Schilling D, Bedke J, Sievert KD, Stenzl A. Incidental prostate cancer at radicalcystoprostatectomy: implications for apex-sparing surgery. BJU Int 2010 Feb;105(4):468-71.http://www.ncbi.nlm.nih.gov/pubmed/20102366

25. Jewett HJ. Proceedings: Cancer of the bladder. Diagnosis and Staging. Cancer 1973 Nov;32(5):1072-4.http://www.ncbi.nlm.nih.gov/pubmed/4757902

26. Husband JE, Olliff JF, Williams MP, Heron CW, Cherryman GR. Bladder cancer: staging with CT andMR imaging. Radiology 1989 Nov;173(2):435-40.http://www.ncbi.nlm.nih.gov/pubmed/2798874

27. Paik ML, Scolieri MJ, Brown SL, Spirnak JP, Resnick MI. Limitations of computerized tomography in

staging invasive bladder cancer before radical cystectomy. J Urol 2000 Jun;163(6):1693-6.http://www.ncbi.nlm.nih.gov/pubmed/10799162

28. Barentsz JO, Jager GJ, Witjes JA, Ruijs JH. Primary staging of urinary bladder carcinoma: the role ofMR imaging and a comparison with CT. Eur Radiol 1996;6(2):129-33.http://www.ncbi.nlm.nih.gov/pubmed/8797968

29. Barentsz JO, Jager GJ, van Vierzen PB, Witjes JA, Strijk SP, Peters H, Karssemeijer N, Ruijs SH.Staging urinary bladder cancer after transurethral biopsy: value of fast dynamic contrast-enhancedMR imaging. Radiology 1996 Oct;201(1):185-93.http://www.ncbi.nlm.nih.gov/pubmed/8816542

30. Mallampati GK, Siegelman ES. MR imaging of the bladder. Magn Reson Imaging Clin N Am 2004Aug;12(3):545-55.http://www.ncbi.nlm.nih.gov/pubmed/15271370

31. Thomsen HS. Nephrogenic systemic fibrosis: history and epidemiology. Radiol Clin North Am 2009Sep;47(5):827-31.http://www.ncbi.nlm.nih.gov/pubmed/19744597



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32. Kundra V, Silverman PM. Imaging in oncology from the University of Texas M. D. Anderson CancerCenter. Imaging in the diagnosis, staging, and follow-up of cancer of the urinary bladder. AJR Am JRoentgenol 2003 Apr 180(4):1045-54.http://www.ncbi.nlm.nih.gov/pubmed/12646453

33. Kim B, Semelka RC, Ascher SM, Chalpin DB, Carroll PR, Hricak H. Bladder tumor staging: comparisonof contrast-enhanced CT, T1- and T2-weighted MR imaging, dynamic gadoliniumenhanced imaging,and late gadolinium-enhanced imaging. Radiology 1994 Oct;193(1):239-45.

http://www.ncbi.nlm.nih.gov/pubmed/809089834. Kim JK, Park SY, Ahn HJ, Kim CS, Cho KS. Bladder cancer: analysis of multi-detector row helical

CT enhancement pattern and accuracy in tumor detection and perivesical staging. Radiology 2004Jun;231(3):725-31.http://www.ncbi.nlm.nih.gov/pubmed/15118111

35. Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Ruijs SJ. Pelvic adenopathy in prostatic and urinarybladder carcinoma: MR imaging with a three-dimensional TI-weighted magnetization-prepared- rapidgradient-echo sequence. AJR Am J Roentgenol 1996 Dec;167(6):1503-7.http://www.ncbi.nlm.nih.gov/pubmed/8956585

36. Yang WT, Lam WW, Yu MY, Cheung TH, Metreweli C. Comparison of dynamic helical CT and dynamicMR imaging in the evaluation of pelvic lymph nodes in cervical carcinoma. AJR Am J Roentgenol 2000Sep;175(3):759-66.

http://www.ncbi.nlm.nih.gov/pubmed/1095446337. Kim SH, Kim SC, Choi BI, Han MC. Uterine cervical carcinoma: evaluation of pelvic lymph node

metastasis with MR imaging. Radiology 1994 Mar;190(3):807-11.http://www.ncbi.nlm.nih.gov/pubmed/8115631

38. Kim SH, Choi BI, Lee HP, Kang SB, Choi YM, Han MC, Kim CW. Uterine cervical carcinoma:comparison of CT and MR findings. Radiology 1990 Apr;175(1):45-51.http://www.ncbi.nlm.nih.gov/pubmed/2315503

39. Oyen RH, Van Poppel HP, Ameye FE, Van de Voorde WA, Baert AL, Baert LV. Lymph node staging oflocalized prostatic carcinoma with CT and CT-guided fine-needle aspiration biopsy: prospective studyof 285 patients. Radiology 1994 Feb;190(2):315-22.http://www.ncbi.nlm.nih.gov/pubmed/8284375

40. Barentsz JO, Engelbrecht MR, Witjes JA, de la Rosette JJ, van der Graaf M. MR imaging of the malepelvis. Eur Radiol 1999;9(9):1722-36.http://www.ncbi.nlm.nih.gov/pubmed/10602944

41. Dorfman RE, Alpern MB, Gross BH, Sandler MA. Upper abdominal lymph nodes: criteria for normalsize determined with CT. Radiology 1991 Aug;180(2):319-22.http://www.ncbi.nlm.nih.gov/pubmed/2068292

42. Swinnen G, Maes A, Pottel H, Vanneste A, Billiet I, Lesage K, Werbrouck P. FDG-PET/CT for thePreoperative Lymph Node Staging of Invasive Bladder Cancer. Eur Urol. 2009 May 18. [Epub ahead ofprint]http://www.ncbi.nlm.nih.gov/pubmed/19477579

43. Kibel AS, Dehdashti F, Katz MD, Klim AP, Grubb RL, Humphrey PA, Siegel C, Cao D, Gao F,Siegel BA. Prospective study of [18F]fluorodeoxyglucose positron emission tomography/computedtomography for staging of muscle-invasive bladder carcinoma. J Clin Oncol 2009 Sep 10;27(26):4314-20

http://www.ncbi.nlm.nih.gov/pubmed/1965207044. Cowan NC, Turney BW, Taylor NJ, McCarthy CL, Crew JP. Multidetector computed tomography

urography (MDCTU) for diagnosing upper urinary tract urothelial tumour. BJU Int 2007 Jun;99(6):1363-70.http://www.ncbi.nlm.nih.gov/pubmed/17428251

45. Van Der Molen AJ, Cowan NC, Mueller-Lisse UG, Nolte-Ernsting CC, Takahashi S, Cohan RH; CTUrography Working Group of the European Society of Urogenital Radiology (ESUR). CT urography:definition, indications and techniques. A guideline for clinical practice. Eur Radiol 2008 Jan;18(1):4-17.http://www.ncbi.nlm.nih.gov/pubmed/17973110

46. Braendengen M, Winderen M, Foss SD. Clinical significance of routine pre-cytectomy bone scans inpatients with muscle-invasive bladder cancer. Br J Urol 1996 Jan;77(1):36-40.http://www.ncbi.nlm.nih.gov/pubmed/8653315

47. Brismar J, Gustafson T. Bone scintigraphy in staging bladder carcinoma. Acta Radiol 1988 Mar-Apr;29(2):251-2.http://www.ncbi.nlm.nih.gov/pubmed/2965914



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48. Lauenstein TC, Goehde SC, Herborn CU, Goyen M, Oberhoff C, Debatin JF, Ruehm SG, BarkhausenJ. Whole-body MR imaging: evaluation of patients for metastases. Radiology 2004 Oct;233(1):139-48.http://www.ncbi.nlm.nih.gov/pubmed/15317952

49. Schmidt GP, Schoenberg SO, Reiser MF, Baur-Melnyk A. Whole-body MR imaging of bone marrow.Eur J Radiol 2005 Jul;55(1):33-40.http://www.ncbi.nlm.nih.gov/pubmed/15950099

5. TREATMENT FAILURE OF NON-MUSCLE

INVASIVE BLADDER CANCER

5.1 High-risk non-muscle-invasive urothelial carcinoma

The recurrence and progression rate of NMIBC is strongly associated with tumour grade and invasion intothe lamina propria. The progression to T2 tumours varies from 6% to 25% in Ta and from 27% to 48% in T1tumours of all grades. Inter- and intra-observer varying abilities in grading as well as staging and completenessof TUR are key variables confounding the results of present long-term studies of TUR, with or without

intravesical therapy. The understaging error in TaT1 tumours of 35% to 62% presented in large cystectomy series is dueto the presence of recurrent tumours of largely unknown pre-cystectomy therapy and the lack of a secondTUR (1-3) (level of evidence: 3). The latter identifies 24% to 49% T2 tumours diagnosed initially as non-muscle-invasive tumours (4,5) (level of evidence: 3). However, in spite of these disadvantages, recent meta-analyseshave shown that intravesical therapy with Bacillus Calmette-Guerin (BCG) maintenance therapy preventsrecurrence (6,7), but not progression. So far, no significant overall- or disease-specific survival advantageshave been proven compared to no intravesical therapy (8-10) (level of evidence: 1).

The disease progression rate is low in patients with small tumours (< 3 cm) and without associated CIS. Twentyper cent of patients progress within 5 years, with approximately 90% of patients keeping their intact bladderduring follow-up of up to 10 years (11) (level of evidence: 2). However, in a recently published prospectivemulticentre trial, the progression rate was significantly lower than previously reported, even when the presenceof concomitant CIS was considered. This was probably due to the combination of a second resection prior toinclusion in the trial and maintenance treatment as part of the protocol (12) (level of evidence: 1b).

Initial cystectomy can be considered based on tumour multiplicity, size, concomitantin situcancer andurothelial tumour of the prostatic urethra (13) (grade of recommendation: C). Although the percentage ofpatients with primary TaT1 tumours and the indication for cystectomy in TaT1 tumours is not specified inlarge cystectomy series, the 10-year recurrence-free survival is approximately 80% and similar to TUR andBCG maintenance therapy (1,3,14,15) (level of evidence: 3). In case of recurrent Ta/T1, mostly associated withCIS, the understaging at time of cystectomy is 34%, but the 10-year survival is not significantly different forpatients with pT1 and pT2 tumours (16) (level of evidence: 3). This is in contrast to an earlier report indicating asignificant worse outcome for patients with previous TUR(s) (17) (level of evidence: 3).

Undoubtedly, patients with muscle-invasive recurrence are best treated with radical cystectomy.

However, the outcome in terms of presence of lymph node metastases and cancer-free survival may be inferiorto patients with the same tumour stage, but who receive radical cystectomy at first presentation (18) (level ofevidence: 3).

There is uncertainty about the treatment of patients who develop tumour recurrence in spite of BCGtherapy because of different BCG therapy schedules and the absence of a uniform definition of BCG failure.It has been indicated that the recurrence (persistence) of tumour at 9 months in spite of BCG therapy isassociated with a 30% chance of invasive tumours and death due to metastatic disease (19) (level of evidence:3). Solsona et al. demonstrated that 80% of patients who had persistent disease at 3 months progressed tomuscle invasive disease (20) (level of evidence: 3). In addition, adequate tissue sampling from the prostaticurethra is an essential factor in considering the outcome of conservative treatment, since urethral tumoursare associated with a significant decrease in tumour-free survival (21) (level of evidence: 3). However, withcareful selection and surveillance a durable complete response can be achieved also in patients diagnosed

with superficial bladder transitional cell carcinoma involving the prostatic urethra (22). Based on these findings,cystectomy should be performed in appropriate patients at least at 9 months, because additional BCG therapyyields a response rate of only 27% to 51% and of unknown duration (23,24) (grade of recommendation: C).Salvage chemotherapy is associated with limited response and should not be offered (25,26) (level of evidence:3).



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8. Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the riskof progression in patients with superficial bladder cancer: a meta-analysis of the published results ofrandomized clinical trials. J Urol 2002 Nov;168(5):1964-70.http://www.ncbi.nlm.nih.gov/pubmed/12394686

9. Bhle A, Bock PR. Intravesical bacille Calmette-Gurin versus mitomycin C in superficial bladdercancer: formal meta-analysis of comparative studies on tumour progression.Urology 2004 Apr;63(4):682-6.

http://www.ncbi.nlm.nih.gov/pubmed/1507287910. Malmstrm PU, Sylvester RJ, Crawford DE, Friedrich M, Krege S, Rintala E, Solsona E, Di Stasi SM,

Witjes JA. An individual patient data meta-analysis of the long-term outcome of randomised studiescomparing intravesical mitomycin C versus bacillus Calmette-Gurin for non-muscle-invasive bladdercancer. Eur Urol 2009 Aug;56(2):247-56.http://www.ncbi.nlm.nih.gov/pubmed/19409692

11. Serretta V, Pavone C, Ingargiola GB, Daricello G, Allegro R, Pavone-Macaluso M. TUR and adjuvantintravesical chemotherapy in T1G3 bladder tumors: recurrence, progression and survival in 137selected patients followed up to 20 years. Eur Urol 2004 Jun;45(6):730-5.http://www.ncbi.nlm.nih.gov/pubmed/15149744

12. Duchek M, Johansson R, Jahnson S, Mestad O, Hellstrm P, Hellsten S, Malmstrm PU; Membersof the Urothelial Cancer Group of the Nordic Association of Urology. Bacillus Calmette-Gurin is

superior to a combination of epirubicin and interferon-alpha2b in the intravesical treatment of patientswith stage T1 urinary bladder cancer. A prospective, randomized, Nordic study. Eur Urol 2010Jan;57(1):25-31.

13. Oosterlinck W, Lobel B, Jakse G, Malmstrm PU, Stckle M, Sternberg C; European Association ofUrology (EAU) Working Group on Oncological Urology. Guidelines on bladder cancer.Eur Urol 2002;41(2):105-12.http://www.ncbi.nlm.nih.gov/pubmed/12074395

14. Pansadoro V, Emiliozzi P, de Paula F, Scarpone P, Pansadoro A, Sternberg CN. Long-term follow-upof G3T1 transitional cell carcinoma of the bladder treated with intravesical bacille Calmette-Gurin:18-year experience. Urology 2002 Feb;59(2):227-31.http://www.ncbi.nlm.nih.gov/pubmed/11834391

15. Margel D, Tal R, Golan S, Kedar D, Engelstein D, Baniel J. Long-term follow-up of patients with StageT1 high-grade transitional cell carcinoma managed by Bacille Calmette-Gurin immunotherapy.Urology 2007 Jan;69(1):78-82.http://www.ncbi.nlm.nih.gov/pubmed/17270621

16. Freeman JA, Esrig D, Stein JP, Simoneau AR, Skinner EC, Chen SC, Groshen S, Lieskovsky G, BoydSD, Skinner DG. Radical cystectomy for high risk patients with superficial bladder cancer in the era oforthotopic urinary reconstruction. Cancer 1995 Sep;76(5):833-9.http://www.ncbi.nlm.nih.gov/pubmed/8625187

17. Stckle M, Alken P, Engelmann U, Jacobi GH, Riedmiller H, Hohenfellner R. Radical cystectomyoftentoo late? Eur Urol 1987;13(6):361-7.http://www.ncbi.nlm.nih.gov/pubmed/3428318

18. Herr HW, Sogani PC. Does early cystectomy improve the survival of patients with high risk superficialbladder tumors? J Urol 2001 Oct;166(4):1296-9.http://www.ncbi.nlm.nih.gov/pubmed/11547061

19. Merz VW, Marth D, Kraft R, Ackermann DK, Zingg EJ, Studer UE. Analysis of early failures afterintravesical instillation therapy with bacille Calmette-Guerin for carcinoma in situ of the bladder.Br J Urol 1995 Feb;75(2):180-4.http://www.ncbi.nlm.nih.gov/pubmed/7850322

20. Solsona E, Iborra I, Rubio J, Casanova J, Almenar S. The optimum timing of radical cystectomy forpatients with recurrent high-risk superficial bladder tumour. BJU Int 2004 Dec;94(9):1258-62.http://www.ncbi.nlm.nih.gov/pubmed/15610101

21. Huguet J, Crego M, Sabat S, Salvador J, Palou J, Villavicencio H. Cystectomy in patients withhigh risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostateinvolvement as a prognostic factor. Eur Urol 2005 Jul;48(1):53-9.http://www.ncbi.nlm.nih.gov/pubmed/15967252

22. Taylor JH, Davis J, Schellhammer P. Long-term follow-up of intravesical bacillus Calmette-Gurin

treatment for superficial transitional-cell carcinoma of the bladder involving the prostatic urethra.Clin Genitourin Cancer 2007 Sep;5(6):386-9.http://www.ncbi.nlm.nih.gov/pubmed/17956711



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23. Brake M, Loertzer H, Horsch R, Keller H. Recurrence and progression of stage T1, grade 3 transitionalcell carcinoma of the bladder following intravesical immunotherapy with bacillus Calmette-Guerin.J Urol 2000 Jun;163(6):1697-701.http://www.ncbi.nlm.nih.gov/pubmed/10799163

24. Pansadoro V, Emiliozzi P, Defidio L, Donadio D, Florio A, Maurelli S, Lauretti S, Sternberg CN. BacillusCalmette-Guerin in the treatment of stage T1 grade 3 transitional cell carcinoma of the bladder:longterm results. J Urol 1995 Dec;154(6):2054-8.

http://www.ncbi.nlm.nih.gov/pubmed/750045725. Malmstrm PU, Wijkstrm H, Lundholm C, Wester K, Busch C, Norln BJ. 5-year followup of a

randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patientswith superficial bladder carcinoma. Swedish-Norwegian Bladder Cancer Study Group. J Urol 1999

Apr;161(4):1124-7.http://www.ncbi.nlm.nih.gov/pubmed/10081852

26. Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety ofvalrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder.The Valrubicin Study Group. J Urol 2000 Mar;163(3):761-7.http://www.ncbi.nlm.nih.gov/pubmed/10687972

27. Jakse G, Hall R, Bono A, Hltl W, Carpentier P, Spaander JP, van der Meijden AP, Sylvester R.Intravesical BCG in patients with carcinoma in situ of the urinary bladder: long-term results of EORTC

GU Group phase II protocol 30861. Eur Urol 2001 Aug;40(2):144-50http://www.ncbi.nlm.nih.gov/pubmed/11528191

28. Losa A, Hurle R, Lembo A. Low dose bacillus Calmette-Guerin for carcinoma in situ of the bladder:long-term results. J Urol 2000 Jan;163(1):68-71.http://www.ncbi.nlm.nih.gov/pubmed/10604316

29. Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, BohlRD, Grossman HB, Beck TM, Leimert JT, Crawford ED. Maintenance bacillus Calmette-Guerinimmunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder:a randomized Southwest Oncology Group Study. J Urol 2000 Apr;163(4):1124-9.http://www.ncbi.nlm.nih.gov/pubmed/10737480

30. de Reijke TM, Kurth KH, Sylvester RJ, Hall RR, Brausi M, van de Beek K, Landsoght KE, CarpentierP; European Organization for the Research and Treatment of Cancer-Genito-Urinary Group. BacillusCalmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ of thebladder: results of a European Organization for the Research and Treatment of Cancer--Genito-Urinary Group Phase III Trial (30906). J Urol 2005 Feb;173(2):405-9.http://www.ncbi.nlm.nih.gov/pubmed/15643181

31. Hudson MA, Herr WH. Carcinoma in situ of the bladder. J Urol 1995 Mar;153(3 Pt 1):564-72.http://www.ncbi.nlm.nih.gov/pubmed/7861485

32. Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bhle A, Palou J. EAU Guidelines on TaT1(Nonmuscle invasive Bladder Cancer). In: EAU Guidelines. Edition presented at the 24th EAUCongress, Stockholm, Sweden, 2009. ISBN-978-90-79754-09-0.http://www.uroweb.org/nc/professional-resources/guidelines/online/

6. NEOADJUVANT CHEMOTHERAPY

The standard treatment for patients with muscle-invasive bladder cancer is radical cystectomy. However,this gold standard only provides 5-year survival in about 50% of patients (1-5). In order to improve theseunsatisfactory results, the use of peri-operative chemotherapy has been explored since the 1980s.

There are many advantages of neoadjuvant chemotherapy, i.e. administering chemotherapy to patientswith operable urothelial carcinoma of the urinary bladder before the planned definitive surgery (or radiation),including: Chemotherapy is delivered at the earliest time-point, when the burden of micrometastatic disease is

expected to be low.

In vivo chemosensitivity is tested. Tolerability of chemotherapy is expected to be better before than after cystectomy.



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The disadvantages of neoadjuvant chemotherapy include: For clinical staging with CT or MR imaging, over- and under-staging is likely to happen with a staging

accuracy of only 70% (6,7). Overtreatment is the possible negative consequence. Delayed cystectomy might compromise the outcome in patients not sensitive to chemotherapy (8,9).

The side-effects of neoadjuvant chemotherapy affecting outcome of surgical morbidity need to be considered.In one randomised trial (10), the same distribution of post-operative complications grade 3-4 was seen in

both trial arms (10). However, generally, pre-operative anaemia and neuropathy was more common in thechemotherapy group. In the combined Nordic trials NCS1+NCS2, (n = 620), neoadjuvant chemotherapy did nothave any major adverse effect on the percentage of performable cystectomies. In the intention to treat analysis,the cystectomy-frequency was 86% in the experimental arm and 87% in the control arm. Still, in crude figures,218 of 306 experimental and cystectomized patients received all 3 chemotherapy cycles (71%). Further 23patients 1 or 2 cycles and 3 patients with greater than 25% dose reduction of cisplatin, translating into 78%receiving any neoadjuvant treatment (11). Several randomised phase III trials investigated the question of whether or not neoadjuvantchemotherapy improved survival, with conflicting results (12-28). Most patients were 70 years old, hada performance status (PS) of 0-1 and a creatinine clearance of > 50-60 mL/minute, due to the kind ofchemotherapy (single-agent cisplatin or cisplatin combination chemotherapy) scheduled. Differences in trial design were mainly the type of chemotherapy (i.e. single-agent cisplatin or

combination chemotherapy) and the number of cycles planned. From the statistical point of view, the studiesdiffered in size, patient characteristics (e.g. clinical T-stages included), and the kind of definitive treatmentallowed (cystectomy or radiotherapy or both). Because of the lack of clarity, even though a considerable number of randomised trials had beenperformed, three meta-analyses were undertaken to answer the very important question of whether or notneoadjuvant chemotherapy prolongs survival (29-31). The first meta-analysis, published in 2003 (29), included 10 randomised trials (except for results of

the INT 0080-study [20]) and showed a 13% reduction in the risk of death, equivalent to 5% absolutebenefit at 5 years (increased overall survival from 45% to 50%).

The second meta-analysis, published in 2004 (30), included 11 of 16 randomised trials with overall

survival data of 2,605 patients. A statistically significant decrease in the risk of death (10%) was seen,corresponding to an absolute improvement in overall survival of 5% (from 50% to 55%).

In the most recent meta-analysis, published in 2005 (32), with updated independent patient data of

11 randomised trials (3005 patients), a statistically significant survival benefit in favour of neoadjuvantchemotherapy was also seen. The results of this analysis confirmed the previously published dataand showed 5% absolute improvement in survival at 5 years. The Nordic combined trial showed anabsolute benefit of 8% in survival at 5 years and 11% in the clinical T3 subgroup, translating intonine patients needed to treat (11). Of note, only cisplatin combination chemotherapy with at least oneadditional chemotherapeutic agent resulted in a meaningful benefit (29,31); the regimens tested wereMVA(E)C, CMV, CM, cisplatin/adriamycin, cisplatin/5-fluorouracil (5-FU), and CarboMV. To date, it isunknown if more modern chemotherapy regimens are as effective.

The presence of micrometastases is postulated to be lower in smaller tumours (T2) compared to moreextensive tumours (T3b-T4b). T4 stage tumours are prone to a higher degree of clinical understaging becausemacrometastic nodal deposits are detected more often in post-cystectomy specimens of these extensive

tumours (32). Further data is in support of neoadjuvant chemotherapy in the subgroup of T2b-T3b t

muscle inv & metastatic bc 2010

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